CN1190186C - Carbohydrate medical solution and sulphite stabilisator in multiple compartment container and use thereof - Google Patents
Carbohydrate medical solution and sulphite stabilisator in multiple compartment container and use thereof Download PDFInfo
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- CN1190186C CN1190186C CNB018088120A CN01808812A CN1190186C CN 1190186 C CN1190186 C CN 1190186C CN B018088120 A CNB018088120 A CN B018088120A CN 01808812 A CN01808812 A CN 01808812A CN 1190186 C CN1190186 C CN 1190186C
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
- A61M1/14—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis
- A61M1/28—Peritoneal dialysis ; Other peritoneal treatment, e.g. oxygenation
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
- A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
- A61J1/14—Details; Accessories therefor
- A61J1/20—Arrangements for transferring or mixing fluids, e.g. from vial to syringe
- A61J1/2093—Containers having several compartments for products to be mixed
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
- A61M1/14—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis
- A61M1/28—Peritoneal dialysis ; Other peritoneal treatment, e.g. oxygenation
- A61M1/287—Dialysates therefor
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
- A61J1/14—Details; Accessories therefor
- A61J1/20—Arrangements for transferring or mixing fluids, e.g. from vial to syringe
- A61J1/2003—Accessories used in combination with means for transfer or mixing of fluids, e.g. for activating fluid flow, separating fluids, filtering fluid or venting
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Abstract
The invention relates to a multiple compartment container for sterile medical solutions, particularly solutions for peritoneal dialysis containing a carbohydrate stabilisation compound, a carbohydrate medical solution containing said carbohydrate stabilisation compound and a method for the preparation thereof.
Description
Technical field
The present invention relates to be equipped with the multicompartment container of sterile medical solutions, wherein at least a solution contains carbohydrate.The invention still further relates to and make carbohydrate stable in sterile medical solutions.
Background of invention
The medical solution for example sterilization of peritoneal dialyses (PD) solution is undertaken by adding energy usually, perhaps forms of radiation energy or heat energy.WO-A-9705852 discloses a kind of multicompartment container that sterilization peritoneal dialyses solution is housed, and it is heating disinfection in autoclave.
In recent years, scientists is recognized the toxicity of the decomposition of chemical compounds of carbohydrate in PD solution.Reports such as Wieslander are compared with the PD solution with filter sterilized, the commercial PD solution of all main trades mark all toxic (Wieslander etc., 1991, Kidney Int, 40:77-79).After with the cell growth medium dilution, on fibroblast, tested PD solution through cultivating.In addition, Wieslander etc. also report, and the glucose degradation product also influences functional response (Wieslander etc., 1995, Peritoneal Dialysis Int, 15 (suppl) that relate to host defense.
Peritoneal dialyses (PD) patient uses 8-20 to rise dialysis solution every day, decides on the treatment situation.So just cause the annual 3-7 of consumption ton solution, wherein contain 1.5-4% glucose (the pure glucose of 50-175 kilogram).(Wieslander, 1996, Nephrol Dial Transplant 11:958-959), if glucose is decomposed, this also means and generates the decomposition of chemical compounds can not ignore quantity.In addition, as you know, in the dialysate injection process, some patient also can agonize.By inference, this misery may be the result (Henderson etc. of glucose degradation, 1985 Frontiersin peritoneal dialysis, winchester edits, New York: Field, Rich, 261-264) and the basic cytotoxicity (BarileFA of these catabolite transmission, 1994, Introduction in vitro cytotoxicity.Florida:CRCPress, 27-35).This just means the basic life process of they influences, is included as the total 26S Proteasome Structure and Function of all living cells for example film integrality, mitochondria activity, perhaps influences the synthetic of protein and DNA.These basic cell functions are kept the specific cell function of body.Therefore, can influence the active glucose degradation product of elementary cell and also may influence single-minded cell function, for example discharge IL-1 β by mononuclear cell.
The known glucose (a kind of penetrating agent) that is generally used for PD solution can degraded generate carbonyl compound, for example formaldehyde, acetaldehyde, methyl-glyoxal, 3-deoxyglucosone and Biformyl.
Sulfite compound is used as antioxidant usually in the emergency case medicine of parenteral, to stop oxidation.The mechanism that carbohydrate decomposes in PD solution shows with the relation of oxidation less, and therefore sulphite is not planned external as antioxidant in the present invention.In addition, antimicrobial or anti-oxidant compounds in the emergency case medicine of parenteral use with concentrated solution usually, it provides 0.5-2 milligram sulphite (SmolinskeS, 1992, Clinical toxicology 30:597-606) for every milliliter of undiluted medicaments injection.For anti-oxidation, in PD solution, do not use such concentrate, because they can give the too many sulphite of patient, cause deleterious toxic action.
Summary of the invention
On the basis of above-mentioned background, an object of the present invention is to provide a kind of multicompartment container that is used for the above-mentioned type sterile medical solutions, the negative interaction of breakdown of carbohydrates and/or catabolite is reduced.Multicompartment container is equipped with at least a sulfite compound in one or more compartments, so that make carbohydrate to decomposing stable or remove the catabolite that produces in sterilization and/or storage process.
The invention still further relates to a kind of like this medical solution, wherein solution contains at least a carbohydrate and at least a sulfite compound, so that make carbohydrate to decomposing stable or remove the catabolite that produces in medical solution sterilization or storage process.
In addition, the invention still further relates to a kind of stable method of carbohydrate containing solution that makes, wherein solution contains at least a sulfite compound, so that make carbohydrate to decomposing stable or remove the catabolite that produces in sterilization and/or storage process.
In addition, the invention still further relates to the application that carbohydrate containing solution is used to prepare multicompartment container.
At last, the invention still further relates to the application that carbohydrate containing solution is used to prepare the multicompartment container that is used for the treatment of the patient who needs it.
Brief description
In the detailed description part of following description, describe the illustrative embodiment with reference to the accompanying drawings in detail the present invention, wherein Fig. 1 is the front view of the multicompartment container of one embodiment of the invention.
Detailed Description Of The Invention
The present invention is used for the treatment of various diseases for example uremia or renal dysfunction, for example comprises and uses abdomen Film dialysis treatment disease.
Definition
Term " medical solution multicompartment container " refers to any container that an above compartment is arranged, Two or three compartments particularly, but be not limited to three compartments. An example is a kind of for peritonaeum The multicompartment container of dialysis, it is equipped with trade mark PhysionealAnd GambrosolTrio sells Medical solution.
Term " medical solution " refers to any solution that is applicable to medical purpose. Wherein carbon can be arranged Hydrate exist and in sterilisation step or storage process carbohydrate stand to decompose, obtain To the disadvantageous catabolite of living cells. The catabolite of expecting for example is more such products, for example Mono-carbonylation compound and dicarbonyl compound, formaldehyde, acetaldehyde, methyl-glyoxal, 3-deoxy-glucose Aldehyde ketone and glyoxal etc. Storage requirement can be any traditional storage requirement, and for example room temperature is 2 years. An example of medical solution is contained in the molten of one or more compartments for what be used for peritoneal dialyses Liquid.
Term " last solution " refers to mix in container by one or more medical solutions and obtains Solution.
Term " peritoneal dialyses solution " refers to contain the solution of electrolyte, buffer agent and osmotically active chemical compound, and wherein electrolyte contains ion for example sodium, potassium, calcium and magnesium ion; Buffer agent contains some components, for example acetate, lactate and bicarbonate like this; The permeability chemical compound is the carbohydrate of stipulating below.Can be at Wieslander etc. as the example of the medical solution of peritoneal dialyses solution, 1991, find among the Kidney Int 40:77-79.Before dialysis, peritoneal dialyses solution can be present in one or more compartments.Under the situation of many compartments, before peritoneal dialyses, each solution is mixed.
Term " carbohydrate " refers to saccharide or sugar-acids, for example glucose, fructose, mannose, glycuronic acid and with the polymer of the ester of saccharide or glucose, fructose, mannose, glycuronic acid and with the glucose of the ester of saccharide or synthesized form, fructose, mannose, glycuronic acid and with the ester of saccharide or derivant and composition thereof.
Term " sulfite compound " refers to a kind of like this chemical compound that contains sulphite, it has for example by making the solution-stabilized character that reduces catabolite content, as what stipulate above, comprise the generation that prevents catabolite or remove the catabolite that in the medical solution sterilization of carbohydrate containing and/or storage process, has generated.
In addition, sulfite compound can be used as antioxidant or is used for eliminating in the body toxic compounds or anaphylaxis chemical compound in the body fluid for example.The example of such toxic compounds or anaphylaxis chemical compound is methyl-glyoxal, 3-deoxyglucosone and Biformyl.The effect of sulfite compound is measured by " analysis of glucose degradation product " method of mentioning in hereinafter " material and method ".The example of such sulfite compound is any have opposite the cation for example sulphite of sodium, potassium, calcium, magnesium and ammonium, for example HSO
3 -, S
2O5
2-And SO
3 2-The example of the sulfite compound that uses is NaHSO
3, Na
2S
2O
5And Na
2SO
3Any other sulfite compounds or its natural or synthetic derivant or its mixture.
Term " stabilisation " refers to prevent the generation of catabolite or remove the catabolite that produces in the sterilization of the medical solution of carbohydrate containing and/or storage process.
Term " carbohydrate breakdown product " refers to the product that produces in carbohydrate solutions in the sterilization of any kind and/or storage process, they are by the carbohydrate product that obtains of breakdown of glucose for example, and to eukaryotic cell and the virose product of prokaryotic cell.Specifically, refer to mono-carbonylation compound and dicarbonyl compound, for example formaldehyde, acetaldehyde, methyl-glyoxal, 3-deoxyglucosone and Biformyl etc.Toxicity can be measured by " in vitro testing toxicity " method of mentioning in hereinafter " material and method ".
Term " sterilisation " refers to any class sterilization, for example radiation, pressurization, heating, UV-ray, radioactive ray, sterilised filtration, microwave radiation or other sterilization methods.In addition, available different approach carries out disinfection, and for example at high temperature the short time sterilizes, sterilizes with high concentration of glucose after sterilizing under the low pH value, removing catalytic specie.
The multicompartment container that is used for medical solution
The present invention relates to be used for the particularly multicompartment container of peritoneal dialyses (PD) usefulness solution of sterile medical solutions, wherein medical appearance liquid is present in one or more compartments.One or more compartments are equipped with carbohydrate and at least a sulfite compound, so that reduce the quantity of the carbohydrate breakdown product that produces in sterilization and/or storage process.In addition, one or more compartments also can be equipped with electrolyte, buffer agent and any other pharmaceutically acceptable additives or other components.
In addition, described container has at least two compartments, preferred three or three above compartments, most preferably three.In at least one compartment, carbohydrate solutions is housed, and at least one compartment, sulfite compound is housed, so that reduce the generation of catabolite or remove the catabolite that has generated by carbohydrate.In addition, " sulfite compound " can be used as antioxidant or is used to eliminate in the body toxic compounds or anaphylaxis chemical compound in the body fluid for example.The single Compartment comtainer used at peritoneal dialyses or the medical solution commonly used in the multicompartment container preferably contain glucose, its in the end the concentration in the solution be 1.5-4.0% (weight), preferred 1.5,2.5 or 4% (weight) (by last solution).
Fig. 1 represents a preferred embodiment of container, in this case, is three compartment pouchs.Bag 1 is become by the plastics continuous tube, and its two ends seal with sealing interface 2,3.
As shown in Figure 1, there are several garlands 4 and hole 5,6,7 in each sealing interface.Garland 4 improves interface 2 stability.Hole 5 in the last interface 2 is used in use hanging sack, and down the hole 6,7 in the interface 3 is used at the fixing sack of preparation manipulation process.
Following interface 3 also has outlet 14, and it links to each other compartment 9 with user, and for example catheter end is in peritoneal dialyses patient's abdominal cavity.Pipe 14 1uer joint end-blocking (not shown in figure 1)s commonly used.In addition, there is filling pipe 12 at interface 3, the medication tube 15 of detachable medicated cap 16 is arranged, if desired, when medicated cap 16 takes off, pipe 15 constitute with the favourable reagent of any kind or medicine for example antibiotics be sent to inlet in the compartment 9.
With welded seal lining 41,42,43 bag 1 is divided into three compartments 9,44,45.The last compartments of separating with welded seal lining 11 44,45 have identical size, and serve as a contrast 42,43 with two oblique welding and separate with following compartment 8.So just form on first compartment 45 on the compartment 44 and second, each is connected by skirt 46,47.Bigger following compartment 9 is equipped with and forms the required electrolyte soluble in water in a known manner of solution, for example NaCl, MgCl
2, lactate etc.
It is about 30% glucose solution that first compartment 44 is equipped with concentration, is about 50% glucose solution and second compartment 45 is equipped with concentration.
When smash connection tube 48 can broken part the time, the material in first compartment 44 just with following compartment 9 in mixing of materials, form the peritoneal dialyses solution that contains 1.5% glucose.If that smashes connection tube 49 can broken part, so the material in the compartment 45 just with compartment 9 in mixing of materials, thereby form the peritoneal dialyses solution that contains 2.5% glucose of having an appointment.If that smashes connection tube 48,49 can broken part, the material in the compartment 44 and 45 just with compartment 9 in mixing of materials, thereby form the dialysis solution that contains 4% glucose of having an appointment.By making at least a glucose contained in the compartment be mixed and made into above-mentioned dialysis solution.
If sack is as nutritive solution, so bigger compartment 9 can only be equipped with NaCl or any other suitable compositions of using at present, but does not conform to glucose.
Should point out that glucose can change the component of similar glucose into as penetrating agent, for example glucose polymer.
In addition, the sterile medical solutions of carbohydrate containing can contain electrolyte, buffer agent for example lactate and any other pharmaceutically acceptable additive.
According to an embodiment of the present invention, carbohydrate is contained in separately in one or more compartments, and the chemical compound of remaining peritoneal dialyses solution is contained in one or more other compartments.Sulfite compound can be present in one or more described compartments or separately exist in one or more compartments.Can or later on sulfite compound be sent in carbohydrate or the electrolyte compartment before sterilization in any.But some components of medical solution or all components and sulfite compound are mixed before peritoneal dialyses must last solution.
If use for example disulfate of single sulphite (monosulphite) chemical compound, preferably the single sulphite with such quantity is added in carbohydrate and/or the electrolyte compartment, so that obtain 0.01-10mM, preferred 0.05-1mM, the last solution of 0.05-0.5mM most preferably.If use dithionite (disulphite), so preferably such quantity is added in the carbohydrate compartment, so that obtain 0.005-5mM, preferably 0.025-0.5mM, 0.025 to 0.25mM last solution most preferably from about.
If use the dithionite chemical compound, so preferably add this quantity, so that obtain using half the last solution of concentration of corresponding single sulfite compound.
The preferred 2.0-7.5 of the pH value of solution, more preferably 2-5.5 even more preferably 3-4, most preferably from about 3.2 in the carbohydrate compartment.The pH value of last solution is preferably 5.0-8.0, more preferably 6.5-8.0,7.0-7.5 or definitely most preferably 7.4 most preferably.
In addition, in an embodiment preferred, will the multicompartment container sterilization of medical solution be housed.Any traditional sterilization method and equipment all can use, those method and apparatus of for example mentioning in the definition of term " sterilisation ".Preferably, sterilization is undertaken by heat treated, most preferably carries out 20 minutes (Ph.Eur. (current)) under about 121 ℃.
Solution
The invention still further relates to a kind of at least a can regulation as top of containing by stablizing the medical solution that reduces the catabolite concentration that generates by carbohydrate or remove the sulfite compound of the catabolite that in carbohydrate containing solution sterilization and/or storage process, has generated.In addition, " sulfite compound " also can be used as antioxidant or can be used for removing in the body toxic compounds or anaphylaxis chemical compound in the body fluid for example.
The invention still further relates to a kind of like this medical solution that is contained in single Compartment comtainer or the multicompartment container, the solution that for example is used for peritoneal dialyses, it contains at least a sulfite compound that can reduce the carbohydrate breakdown that exists in the solution that is exposed in the sterilization.
If use for example bisulfites of single sulfite compound, so preferably this quantity is added in carbohydrate and/or the electrolyte compartment, be 0.01-10, preferred 0.05-1,0.05 to 0.5mM last solution most preferably from about so that obtain concentration.If the use dithionite so preferably is added to this quantity in the carbohydrate compartment, be 0.005-5, preferred 0.025-0.5, the last solution of 0.025-0.25mM most preferably so that obtain concentration.
If the use dithionite so preferably adds this quantity, so that obtain using half the last solution of concentration of corresponding single sulfite compound.
The pH value of carbohydrate solutions is unimportant, can be in any scope, and the pH value that is fit to is 2.0-7.5, more preferably 2-5.5 even more preferably 3-4 even more preferably from about 3.2.The pH value of last solution is preferably 5.0-8.0, more preferably 6.5-8.0,7.0-7.5 most preferably.
Preferably, medical solution is a sterile medical solutions.
In addition, can or later on sulfite compound be added in the carbohydrate solutions before sterilization.
In addition, carry out disinfection, as stipulating in the above-mentioned term " sterilisation " with any traditional sterilization method.Preferably, by at 100-150 ℃ of following heat treatment 1-130 minute, more preferably at 121 ℃ of following heat treatments carried out disinfection in 20 minutes (Ph.Eur. (current)).
Solution can be any medical solution that contains carbohydrate and contain or do not contain other components.Preferably, solution is a kind of like this medical solution, for example is used for the solution of peritoneal dialyses, the single Compartment comtainer that is preferred for peritoneal dialyses or multicompartment container, more preferably two Compartment comtainers or three Compartment comtainers even the more preferably medical solution of three Compartment comtainers.The medical solution that is used for peritoneal dialyses preferably contains the glucose of this quantity, so that in the end obtains 1.5-4% in the solution, the concentration of glucose (by whole last solution) of preferred about 1.5,2.5 or 4% (weight).
In addition, medical solution is a kind of solution that is used to remove interior toxic compounds of body or anaphylaxis chemical compound, preferred a kind of medical solution that is used to remove interior toxic compounds of body fluid or anaphylaxis chemical compound.
Method
The invention still further relates to and a kind ofly in sterilization and/or storage process, make carbohydrate in the medical solution decomposing stable or removing the method for the catabolite that carbohydrate produces, described method is included in before the sterilization or later on sulfite compound is added in the solution, so that reduce breakdown of carbohydrates in the medical solution.
Preferably, described method is used to prepare the medical solution that peritoneal dialyses is used.
Even more preferably, medical solution is used for the multicompartment container of peritoneal dialyses, for example three Compartment comtainers.
Preferably, described method is used to prepare the multicompartment container that is used for peritoneal dialyses, wherein sulfite compound can be added in the carbohydrate compartment of many compartments or be added in the electrolyte compartment.
If use single sulfite compound, so preferably the single sulfite compound with this quantity is added in the carbohydrate compartment, so as to obtain it in the end the concentration in the solution be 0.01-10, preferred 0.05-1,0.05-0.5mM most preferably.
If use the dithionite chemical compound, so preferably this quantity is added in the carbohydrate solutions so that obtain it in the end the concentration in the solution be 0.005-5, preferred 0.025-0.5,0.025-0.25mM most preferably.
When using dithionite, the also preferred dithionite that adds this quantity so that make it in the end the concentration in the solution be half of the concentration of using corresponding single sulfite compound.
The pH value of carbohydrate compartment is preferably 2.0-7.5, more preferably 2-5.5 even more preferably 3-4, and most preferably from about 3.2.
More preferably, described method is used for preparation sterilization multicompartment container.
In addition, the sterilization before or later on sulfite compound is added in the carbohydrate solutions.
In addition, carry out disinfection, as stipulating in the above-mentioned term " sterilisation " with any traditional sterilization method.Preferably, be used in 100-150 ℃ of heat treated 1-130 minute, preferably at 20 minutes method of 121 ℃ of following heat treated carry out disinfection (Ph.Eur. (current)).
Method of the present invention is used for medical solution, and wherein medical solution need be with the sterilization of the method stipulated in the term " sterilisation ", and described method is preferred for preparing the medical solution that is used for peritoneal dialyses etc.By before sterilization or later on a spot of sulfite compound is added in the solution, make carbohydrate resolve in solution that deleterious chemical compound is prevented from or deleterious chemical compound is eliminated.Preferably, the medical solution that is used for peritoneal dialyses preferably contains the glucose of this quantity, is 1.5-4% so that make the concentration of glucose in the last solution, preferred about 1.5,2.5 or 4% (weight).
In addition, sulfite compound can be used as antioxidant or is used to remove in the body toxic compounds or anaphylaxis chemical compound in the body fluid for example.
In addition, the invention provides the application that carbohydrate containing solution is used to prepare the multicompartment container that is applicable to peritoneal dialyses, preferred three Compartment comtainers.
Specifically, the invention provides the application that carbohydrate containing solution is used to prepare the multicompartment container of the animal that is used for the treatment of needs.
Material and method
The mensuration of glucose degradation product:
Chemicals: acetonitrile (Lab Scan, Ireland) and methanol (Lab Scan Ireland) is the HPLC level.2, the 3-diaminonaphthalene is by ICN, and USA provides.56% (w/w) 3-deoxyglucosone is synthetic by T.Henle Technische Univerit t Dresden.Sodium phosphate p.a. and 30% (weight/volume) Biformyl is provided by Merck (Germany).40% (weight/volume) methyl-glyoxal, 2, (2,4-DNpH) with 1, the 2-phenylenediamine is provided by Sigma Chemical (USA) 4-dinitrophenyl hydrazine.Acetaldehyde p.a. is provided by Fluka (Germany).
Equipment: two HPLC systems are used to measure degradation of glucose product (GDP).A HPLC is made up of the Hewlett Packard liquid chromatography series 1050 that UV-assessor and Autosampler are housed.Second HPLC system is made up of the Hewlett Packard liquid chromatography series 1100 that Autosampler and water refractive index evaluation type 410 is housed.Hewlett Packard ChemStation software rev.A.06.03, NT4.0 is used for date processing.
The mensuration of 3-deoxyglucosone (3-DG):
With 2, the 3-diaminonaphthalene is measured the 3-deoxyglucosone as derivating agent.Before analyzing, with 50 times of diluted samples, making cumulative volume is 1 milliliter.The standard of preparation is 1-6 μ M.By with 100 microlitres 0.1%2, the 3-diaminonaphthalene is added at room temperature to cultivate in the dark then in 1 ml sample and came preparation standard and sample in 16 hours.Analytical column is Water Symmetry C18 post (5 microns, 4.6 millimeters of 25 cm x).The acetonitrile/water that use is successively decreased under the constant flow velocity of 1.0 ml/min that is eluted in of material is carried out.The ratio of acetonitrile/water (volume/volume) is initially 25/75, and is 60/40 when being 25/75,15 minute after 12 minutes, and is 60/40 successively decreasing when stopping 30 minutes.In 268 nanometers, is 20 microlitres and inject volume with wavelength set.The quantitative limit is 1 μ M.
The mensuration of acetaldehyde and formaldehyde: will measure 20 times of the diluted samples of acetaldehyde before analyzing, making cumulative volume is 4 milliliters.Acetaldehyde prepares as the derivant of hydrazone, uses 2, and 4-DNpH is as derivating agent.Standard is prepared as 1.1-11.4 μ M acetaldehyde and 1.7-16.7 μ M formaldehyde.By with 2 milliliter of 0.08% (weight/volume) 2,4-DNpH is added in 4 milliliters of each samples and comes preparation standard and sample.Sample is gone up at Solid-Phase Extraction C18 post (Bond Elut LRC200 milligram/3 milliliters) and is concentrated, 1.6 milliliters of acetonitrile eluting of reuse after water cleans.Analytical column is Supelco C18 post (5 microns, 4.6 millimeters of 15 cm x).Being eluted under the constant flow velocity of 1.7 ml/min of material carried out with the linear decrease acetonitrile/water.Acetonitrile/water is initially 35/65 than (volume/volume), is 80/20 successively decreasing after stopping 12 minutes.In 240 nanometers, injecting volume is 20 microlitres with wavelength set.The quantitative limit is 1.1 μ M acetaldehyde and 1.7 μ M formaldehyde.
The measurement of Biformyl and methyl-glyoxal: use 1, the 2-phenylenediamine is measured Biformyl and methyl-glyoxal with quinoxaline.Make 3.5-51.7 μ M Propylene Glycol and make standard.By with 0.6 milliliter of 0.4% (volume/volume) 1, the 2-phenylenediamine is added in 1 milliliter of every kind of sample and comes preparation standard and sample.Analytical column is Supelco C18 post (5 microns, 4.6 millimeters of 25 cm x).Being eluted under the constant flow velocity of 1.0 ml/min of material carried out with the mobile phase of initial 25% (volume/volume) acetonitrile and 75% (weight/volume) 0.05M sodium phosphate.Successively decreasing 6 minutes the time, mobile phase is 30% acetonitrile and 70% millipore water, and is successively decreasing when stopping 9 minutes, and ratio is 25/75.In 312 nanometers, injecting volume is 20 microlitres with wavelength set.The quantitation limit of Biformyl is 3.5 μ M, and the quantitation limit of methyl-glyoxal is 2.8 μ M.
Detect cytotoxicity in vitro
The medical solution that will be used for peritoneal dialyses mixes and adds 10% (volume/volume) fetus sura serum (Wieslandr etc., 1991, Kidney Int 40:77-79) with a cell growth medium.At l cell L-929 (CCL-1; ATTC, Rockville, MD, USA) go up the elementary cell toxicity of measuring the medical solution that is used for peritoneal dialyses, as (Wieslander etc., 1993 of early describing, and be expressed as inhibitory rate of cell growth (ICG) Advances in Peritoneal Dialys 9:31-35).
Multicompartment container as shown in Figure 1 is equipped with following medical solution in three compartments 44,45 and 9.
Glucose 30%
Calcium 20mM
Magnesium 5mM
Sodium 132mM
Bisulfites 1mM
PH value 3.2
Glucose 50%
Calcium 33mM
Magnesium 8mM
Sodium 132mM
Bisulfites 1mM
PH value 3.2
Bicarbonate 40mM
Sodium 132mM
PH value 6.7
By the mixing of materials of compartment 44 and 9, make the last solution that is applicable to peritoneal dialyses of following concentration:
Glucose 1.5%
Calcium 1.0mM
Bicarbonate 38mM
Sodium 132mM
Magnesium 0.25mM
Bisulfites 0.05mM
By the mixing of materials of compartment 45 and 9, make the last solution that is applicable to peritoneal dialyses of following concentration:
Glucose 2.5%
Calcium 1.65mM
Bicarbonate 38mM
Sodium 132mM
Magnesium 0.4mM
Bisulfites 0.05mM
The mixing of materials of material and compartment 9 by compartment 44 and 45 makes the last solution that is suitable for peritoneal dialyses of following concentration:
Glucose 4.0%
Calcium 2.5mM
Bicarbonate 36mM
Sodium 132mM
Magnesium 0.6mM
Bisulfites 0.1mM
Multicompartment container as shown in Figure 1 is equipped with following medical solution in three compartments 44,45 and 9.
Glucose 30%
Calcium 20mM
Magnesium 5mM
Sodium 132mM
PH value 3.2
Glucose 50%
Calcium 33mM
Magnesium 8mM
Sodium 132mM
PH value 3.2
Bicarbonate 40mM
Sodium 132mM
Bisulfites 0.1mM
PH value 6.7
By the mixing of materials of compartment 44 and 9, make the last solution that is applicable to peritoneal dialyses of following concentration:
Glucose 1.5%
Calcium 1.0mM
Bicarbonate 38mM
Sodium 132mM
Magnesium 0.25mM
Bisulfites 0.095mM
By the mixing of materials of compartment 45 and 9, make the last solution that is applicable to peritoneal dialyses of following concentration:
Glucose 2.5%
Calcium 1.65mM
Bicarbonate 38mM
Sodium 132mM
Magnesium 0.4mM
Bisulfites 0.095mM
The mixing of materials of material and compartment 9 by compartment 44 and 45 makes the last solution that is applicable to peritoneal dialyses of following concentration:
Glucose 4.0%
Calcium 2.5mM
Bicarbonate 36mM
Sodium 132mM
Magnesium 0.6mM
Bisulfites 0.090mM
The solution that is used for embodiment 3 and 4 is embodiment 1 and 2 solution of describing, and different is, uses 50% glucose in slightly different all the glucose compartments of compartment volumes.
Prepared two not on the same group solution, electrolyte compartment that 1.875 liters of volumes are arranged, one for being added with the compartment that glucose is housed of varying number bisulfites, and this volume is 125 milliliters.Solution was sterilized 1 hour sterilization back remix down at 121 ℃.Mixing the electrolytical concentration in back is 132mM Na
+, 1.35mM Ca
2+, 0.25mM Mg
2+, 95.2mM Cl
-With the 40mM lactate.
In the end in the solution, the concentration of glucose is 4% (weight/volume), and the concentration of sulphite is 0,0.01,0.05,0.1,0.2 and 0.5mM.
Pressing the cytotoxicity of mentioning in " material and method " that detects through disinfectant solution in test tube analyzes.The result who detects shows that the increase of sodium acid sulfate descends the ICG value, and this content that just means deleterious catabolite after adding sodium acid sulfite reduces.
As described in example 3 above, different is that sulphite is added in the electrolyte compartment.The electrolyte in the solution in the end, the concentration of glucose and sulphite is identical with embodiment 3.Pressing embodiment 3 through disinfectant solution analyzes.Testing result shows that the increase of sodium sulfite descends the ICG value, and this content that just means deleterious catabolite reduces.
To contain 132mM Na
+, 1.35mM Ca
2+, 0.25mM Mg
2+, 95.2mM Cl
-, 40mM lactate and 1.5% glucose three kinds of solution 121 ℃ of sterilizations 1 hour down.Mix with sodium sulfite through disinfectant solution, obtain 3 different concentration of sodium sulfite (0,0.5,1mM).
Contain 132mM Na
+, 1.35mM Ca
2+, 0.25mM Mg
2+, 95.2mM Cl
-, 40mM lactate and 1.5% glucose 3 kinds of solution mix with sodium acid sulfite, obtain different acidic sulfurous acid na concn (0,0.5,1mM), then 121 ℃ of sterilizations 1 hour down.
Pressing the detect cytotoxicity and mensuration acetaldehyde and formaldehyde mentioned in " material and method " through disinfectant solution in test tube analyzes.The result who is obtained by Cytotoxic detection in the test tube shows that the increase of sodium acid sulfite causes the ICG value to descend, and this content that just means deleterious catabolite reduces.The result who is obtained by mensuration acetaldehyde and formaldehyde shows, descends in aldehyde in solution that contains sodium acid sulfite and content of formaldehyde, even drops to below the detectable limit.
Claims (19)
1. the multicompartment container that is used for sterile medical solutions, wherein said solution are present in two or more compartments, and at least a in the described solution is carbohydrate, it is characterized in that, at least a sulphite is present in one or more described compartments,
Wherein said sulphite is selected from HSO
3 -, S
2O
5 2-Or SO
3 2-Or its mixture, contain opposite cation, preferred NaHSO
3, Na
2S
2O
5Or Na
2SO
3Or its mixture,
When described sulfite compound is single sulfite compound, in described container the total amount of single sulfite compound equal the 0.05-1 mM/liter, preferred 0.05-0.5 mM/liter,
When described sulfite compound is the dithionite chemical compound, in described container the total amount of dithionite chemical compound equal the 0.025-0.5 mM/liter, preferred 0.025-0.25mmol/l.
2. according to the multicompartment container of claim 1, wherein the pH value of mixed solution is 5.0-8.0, more preferably 6.0-8.0, most preferably 7.0-7.5 in described container.
3. according to each multicompartment container among the claim 1-2, wherein said carbohydrate is a glucose, and the total amount of glucose is about 4% (weight) of solution total amount in the described container in described container.
4. according to each multicompartment container among the claim 1-3, wherein said carbohydrate is not present in all compartments, preferably exists only among in two compartments of two compartment pouchs, or exists only among in three compartments of three compartment pouchs two.
5. according to the multicompartment container of claim 4, the pH value that wherein contains the described compartment of described carbohydrate is 2.0-7.5, preferred 2.0-5.5, more preferably 3-4, most preferably from about 3.2.
6. according to the multicompartment container of claim 4 or 5, wherein said sulphite is single sulfite compound, and the described dense single sulphite in wherein said different solutions mixing back gets solution to the end, and the concentration of its single sulfite compound is 0.05-1mM, preferred 0.025-0.25mM.
7. according to the multicompartment container of claim 4 or 5, wherein said sulphite is dithionite, and the described dense dithionite in wherein said different solutions mixing back gets solution to the end, and its dithionite compound concentrations is 0.025-0.5mM, preferred 0.025-0.25mM.
8. according to each multicompartment container among the claim 4-7, wherein said carbohydrate is a glucose, and described container is three compartment pouchs, wherein by the weight of glucose, after described different solutions mixes glucose in the end the concentration in the solution be 1.5-4%, preferred about 1.5,2.5 or 4% (weight).
9. according to each multicompartment container among the claim 1-8, wherein said container is sterilized with heat treated.
10. according to each multicompartment container among the claim 1-9, wherein said multicompartment container is equipped with and is used for mixing the medical solution for preparing the last solution that is used for peritoneal dialyses by two or more described medical solution.
11. a sterile medical solutions, described medical solution contain carbohydrate, at least a HSO that is selected from opposite cation
3 -, S
2O
5 2-Or SO
3 2-Sulfite compound or its mixture, preferred NaHSO
3, Na
2S
2O
5Or Na
2SO
3Or its mixture, wherein said sulfite compound is the single sulfite compound of concentration 0.05～1mM or the dithionite chemical compound that concentration is 0.025～0.5mM.
12. according to the sterile medical solutions of claim 11, wherein said sulfite compound is single sulfite compound, its concentration is 0.05-0.5mM.
13. according to the sterile medical solutions of claim 11 or 12, wherein said solution is heated sterilization.
14. according to each sterile medical solutions among the claim 11-13, wherein said solution is the solution that is used for peritoneal dialyses.
15. according to each sterile medical solutions among the claim 11-14, wherein said solution is used for three Compartment comtainers.
16. stable method of sterile medical solutions that makes carbohydrate containing, wherein at least a sulfite compound is added in the described solution, if described sulfite compound is single sulfite compound, its concentration is 0.05-1, preferred 0.05-0.5mM so, if described sulfite compound is the dithionite chemical compound, its concentration is 0.025-0.5, preferred 0.025-0.25mM so.
17. according to the method for claim 16, wherein said sulfite compound is selected from the HSO of opposite cation
3 -, S
2O
5 2-Or SO
3 2-Or its mixture, preferred NaHSO
3, Na
2S
2O
5Or Na
2SO
3Or its mixture.
18. according to the method for claim 16 or 17, wherein said solution is heated sterilization.
19. the sterile medical solutions of each carbohydrate containing is used for preparing each the application of multicompartment container of claim 1-10 among the claim 11-15.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE0001939A SE0001939D0 (en) | 2000-05-25 | 2000-05-25 | Medical solution and use thereof |
| SE00019398 | 2000-05-25 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1427716A CN1427716A (en) | 2003-07-02 |
| CN1190186C true CN1190186C (en) | 2005-02-23 |
Family
ID=20279819
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB018088120A Expired - Fee Related CN1190186C (en) | 2000-05-25 | 2001-05-18 | Carbohydrate medical solution and sulphite stabilisator in multiple compartment container and use thereof |
Country Status (11)
| Country | Link |
|---|---|
| US (1) | US20030159953A1 (en) |
| EP (1) | EP1289496A1 (en) |
| JP (1) | JP2003534052A (en) |
| KR (1) | KR20030001486A (en) |
| CN (1) | CN1190186C (en) |
| AU (2) | AU6091801A (en) |
| BR (1) | BR0111095A (en) |
| CA (1) | CA2403574A1 (en) |
| MX (1) | MXPA02010839A (en) |
| SE (1) | SE0001939D0 (en) |
| WO (1) | WO2001089478A1 (en) |
Families Citing this family (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP4882054B2 (en) * | 2000-09-13 | 2012-02-22 | 独立行政法人科学技術振興機構 | Peritoneal dialysate and preparation method thereof |
| SE523153C2 (en) * | 2000-12-28 | 2004-03-30 | Gambro Lundia Ab | Method of detoxification of medical solution |
| DE10134568C2 (en) * | 2001-07-16 | 2003-07-24 | Inst Chemo Biosensorik | Method for the quantitative determination of alpha-oxoaldehyde |
| TWI319984B (en) * | 2003-06-06 | 2010-02-01 | Sterile combined preparation | |
| SE0400523D0 (en) * | 2004-03-01 | 2004-03-01 | Gambro Lundia Ab | A medical solution, a method for producing said medical solution and use thereof |
| US20050276868A1 (en) * | 2004-06-10 | 2005-12-15 | Bart Degreve | Bicarbonate-based peritoneal dialysis solutions |
| SE0402507D0 (en) | 2004-10-14 | 2004-10-14 | Gambro Lundia Ab | Medical solution, method of preparation and use thereof |
| US7935070B2 (en) * | 2005-01-28 | 2011-05-03 | Fresenius Medical Care North America | Systems and methods for dextrose containing peritoneal dialysis (PD) solutions with neutral pH and reduced glucose degradation product |
| AU2012201932B2 (en) * | 2005-01-28 | 2015-01-22 | Fresenius Medical Care Holdings, Inc | Systems and methods for delivery of peritoneal dialysis (PD) solutions |
| US20090187139A1 (en) * | 2006-02-08 | 2009-07-23 | Debiotech S.A. | Peritoneal dialysis system |
| US9004761B2 (en) | 2006-05-01 | 2015-04-14 | Baxter International Inc. | Multiple chamber container with mistake proof administration system |
| NZ574925A (en) * | 2007-07-27 | 2013-02-22 | Fresenius Med Care Hldg Inc | Container system for peritoneal dialysis solutions having a first a compartment containing with PD osmotic agent and a second compartment with a PD buffer agent |
| US9585810B2 (en) | 2010-10-14 | 2017-03-07 | Fresenius Medical Care Holdings, Inc. | Systems and methods for delivery of peritoneal dialysis (PD) solutions with integrated inter-chamber diffuser |
| NO20150142A1 (en) * | 2015-01-30 | 2016-08-01 | Pronova Biopharma Norge As | Enteral feeding device |
| KR102657465B1 (en) * | 2021-03-04 | 2024-04-16 | (주) 테크윈 | Stabilization method of persulfate solution |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4339433A (en) * | 1981-01-09 | 1982-07-13 | Baxter Travenol Laboratories, Inc. | Additives for peritoneal dialysis solutions |
| US6306836B1 (en) * | 1994-01-21 | 2001-10-23 | Baxter International Inc. | Peritoneal dialysis solutions containing maltodextrins and amino acids |
| SE510030C2 (en) * | 1995-08-08 | 1999-04-12 | Gambro Ab | Method of mixing sterile medical solution and container for carrying out the procedure |
-
2000
- 2000-05-25 SE SE0001939A patent/SE0001939D0/en unknown
-
2001
- 2001-05-18 MX MXPA02010839A patent/MXPA02010839A/en unknown
- 2001-05-18 CA CA002403574A patent/CA2403574A1/en not_active Abandoned
- 2001-05-18 CN CNB018088120A patent/CN1190186C/en not_active Expired - Fee Related
- 2001-05-18 BR BR0111095-0A patent/BR0111095A/en not_active IP Right Cessation
- 2001-05-18 KR KR1020027015215A patent/KR20030001486A/en not_active Application Discontinuation
- 2001-05-18 AU AU6091801A patent/AU6091801A/en active Pending
- 2001-05-18 WO PCT/SE2001/001125 patent/WO2001089478A1/en active IP Right Grant
- 2001-05-18 AU AU2001260918A patent/AU2001260918B8/en not_active Ceased
- 2001-05-18 JP JP2001585723A patent/JP2003534052A/en active Pending
- 2001-05-18 US US10/275,104 patent/US20030159953A1/en not_active Abandoned
- 2001-05-18 EP EP01934766A patent/EP1289496A1/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| CA2403574A1 (en) | 2001-11-29 |
| AU2001260918B2 (en) | 2005-08-11 |
| AU2001260918B8 (en) | 2005-12-08 |
| BR0111095A (en) | 2003-04-08 |
| US20030159953A1 (en) | 2003-08-28 |
| JP2003534052A (en) | 2003-11-18 |
| KR20030001486A (en) | 2003-01-06 |
| WO2001089478A1 (en) | 2001-11-29 |
| SE0001939D0 (en) | 2000-05-25 |
| AU6091801A (en) | 2001-12-03 |
| CN1427716A (en) | 2003-07-02 |
| MXPA02010839A (en) | 2004-02-26 |
| EP1289496A1 (en) | 2003-03-12 |
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